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Subjects

Abstract

Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar. Restricted access to such memories can present a risk for psychiatric disorders and hamper their treatment. To better understand the mechanisms underlying state-dependent fear, we used a mouse model of contextual fear conditioning. We found that heightened activity of hippocampal extrasynaptic GABAA receptors, believed to impair fear and memory, actually enabled their state-dependent encoding and retrieval. This effect required protein kinase C-βII and was influenced by miR-33, a microRNA that regulates several GABA-related proteins. In the extended hippocampal circuit, extrasynaptic GABAA receptors promoted subcortical, but impaired cortical, activation during memory encoding of context fear. Moreover, suppression of retrosplenial cortical activity, which normally impairs retrieval, had an enhancing effect on the retrieval of state-dependent fear. These mechanisms can serve as treatment targets for managing access to state-dependent memories of stressful experiences.

Acknowledgements

We thank W. Xu and T.C. Sudhof (Stanford University) for providing us with the SynaptoTag viral vector, C. Fernandez-Hernando (Yale School of Medicine) for providing pMIRNA1/pCDH plasmids encoding miR-33 and scrambled miRNA, and the Genomic Core (Northwestern University) for generating lentiviral vectors containing miR-33 and scrambled constructs. We also thank B. Frick and F. Kassam for their help with the behavioral experiments. This work was supported by US National Institutes of Health grants NIH/NIMH MH078064 (J.R.), NIH/NINDS NS061963 and NS087479 (G.M.G.S.), and a Ken and Ruth Davee Award for Innovative Investigations in Mood Disorders, (J.R. and V.J.).

Author information

Affiliations

Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

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Contributions

V.J. and J.R. designed the experiments, analyzed the data and wrote the manuscript. V.J. performed the experiments. K.A.C. and K.L. performed some of the behavioral and biochemical experiments. H.J.C. and A.L.G. helped with the biochemical experiments. N.Y. and G.M.G.S. performed the electrophysiological recordings.